The International Cancer Genome Consortium
(ICGC) has performed whole exome sequencing of 142 human Pancreatic Ductal
Adenocarcinomas1 identifying a number of significantly
altered genes in pancreas cancer, including SOX9, which was somatically mutated
or copy number altered in 10% of informative patient tumors. SOX9 is a known master transcription
factor in embryonic differentiation of pancreatic duct cells and contributes to
ductal metaplasia in adult pancreas2. Integration of the ICGC data with a large
functional shRNA screen of ~12,000 genes in 102 cancer cell lines 3, supports the hypothesis that SOX9 is a high-ranking oncogene in
pancreas cancer.

By immunohistochemistry on ICGC tissue
microarrays, we confirm that SOX9 is strongly expressed in human pancreas
cancer and metaplastic regions adjacent to the tumour. Western blot analysis of a large panel
of pancreas cancer cell lines reveals that high expression of SOX9 is
coincident with a K-Ras mutated genotype, reflective of >90% of the tumours. In agreement
with these observations, metaplastic pancreatic epithelial cells isolated from
a K-Ras mutant mouse express higher levels of Sox9 than their wild type
counterpart.

ICGC patients were subject to microarray analysis,
and by comparing the highest and lowest SOX9-expressing patients, SOX9 was found
to act as a positive regulator of many common cancer biology pathways including
EGFR, MAPK and cell cycle regulation. This observation is also reflected in the
pancreatic tumour cell lines, where reduced phosphorylated EGFR and ERK expression correlates with low SOX9 expression.

In conclusion, we have identified SOX9 as a
novel gene altered in pancreatic cancer in clinical samples, cell lines and
mouse models of pancreatic cancer.
We have linked the upregulation of SOX9 to activating mutations in K-Ras
and enhanced EGFR signalling, both implicated in pancreatic carcinogenesis.